Deep brain stimulation (DBS) within the basal ganglia complex is an effective neurosurgical approach for treating motoric symptoms of Parkinson's disease (PD). Elucidating DBS mechanisms for improving outcomes in PD and other targeted disorders has become a critical clinical goal in stereotactic and functional neurosurgery. We propose to address this issue by combining for the first time two powerful technologies, notably functional Magnetic Resonance Imaging (fMRI) and in vivo neurochemical monitoring to investigate DBS-mediated activation of basal ganglia network circuitry. For this purpose, we have developed an MRI-compatible wireless monitoring device to obtain chemically resolved neurotransmitter measurements at implanted microsensors in a large mammalian model (rhesus monkey). This device supports an array of electrochemical measurements that includes fast-scan cyclic voltammetry (FSCV) for real-time simultaneous in vivo monitoring of dopamine and adenosine release at carbon-fiber microelectrodes as well as fixed potential amperometry for monitoring of glutamate at enzyme-linked biosensors. Using electrophysiological targeting of the STN to implant appropriately scaled-down human DBS electrodes, our rhesus monkey model will enable us to employ fMRI to initially determine the major sites of activation in the basal ganglia during application of clinically-defined "therapeutic" (tDBS) versus "non-therapeutic" (nDBS) STN stimulation. We will then electrochemically monitor extracellular levels of glutamate, dopamine and adenosine release evoked by STN DBS in the brain areas identified by fMRI activation. Lastly, we propose to combine fMRI and FSCV recordings in the rhesus monkey to confirm a causal relationship between glutamate, dopamine and/or adenosine release and the fMRI-identified anatomical sites in the basal ganglia complex by determining the consequences of dopamine depletion and repletion mimicking advanced PD and pharmacological treatment of the disease, as well as adenosine depletion. The three Specific Aims are (1) identify using fMRI brain regions within the basal ganglia complex activated by STN DBS, (2) quantify glutamate, dopamine and adenosine release evoked by STN DBS of the brain region(s) identified by fMRI, and (3) correlate STN DBS-evoked glutamate, dopamine and adenosine release in the regions identified by fMRI with simultaneous fMRI before, during, and after pharmacological depletion and restoration of dopamine, and reductions in adenosine. We believe that the simultaneous combination of fMRI and electrochemistry offer a new and exciting approach that provides complementary anatomical mapping and neurochemical monitoring implicated in the therapeutic actions of STN DBS. PUBLIC HEALTH RELEVANCE: Deep brain stimulation (DBS) is an effective neurosurgical treatment for Parkinson's disease and other debilitating neuropathologies. The goal of this proposal is to elucidate the therapeutic actions of DBS by combining for the first time fMRI and in vivo electrochemical protocols in a rhesus monkey model to achieve complementary anatomical mapping and neurochemical monitoring.